The serotonin transporter (SERT) is an integral membrane glycoprotein that is responsible for the reuptake of serotonin from the synapse. Drugs that inhibit the SERT are effective in several psychiatric disorders including depression. Recent studies have shown that the SERT can be regulated in vitro. Less is understood about its acute or chronic regulation in vivo. Different approaches have been used to address this issue, with inconclusive results. We have used in vivo chronoamperometry, a fast voltammetric technique, to demonstrate that there are areas in brain such as the CA3 region of the hippocampus, where the active clearance of exogenously ejected serotonin is primarily a function of SERT activity. This technique, then, is capable of generating rapid kinetic, quantitative measures of SERT function in vivo. In the proposed experiments, we will use this approach to study if long term administration of two different selective serotonin reuptake inhibitors (SSRIs), paroxetine and fluoxetine, produce a time-dependent subsensitivity of the SERT. The influence of treatment parameters such as route of administration, duration of administration, and drug-free washout period will be evaluated. Based on our preliminary data, we will explore if activation of terminal 5-HT1B autoreceptors alters the kinetics of SERT function in vivo. If so, then we will examine whether such a phenomenon impacts on any apparent regulatory effect of chronic SSRI treatment on SERT activity. In addition to examining the CA3 region, two other brain areas where the active clearance of 5-HT is due exclusively to the SERT will be studied. These experiments provide a new approach to study whether the SERT, a primary target for several types of antidepressants, is capable of being regulated either acutely or chronically in vivo.